More Antibodies With Longer Intervals Between COVID Vaccine Doses

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LISBON, Portugal — An overall ninefold increase in COVID-19 antibody levels can be seen with a longer interval between first and second doses of the Pfizer/BioNTech (BNT162b2) vaccine in people without prior infection, according to data from the UK government's SIREN (SARS-CoV-2 Immunity and Reinfection Evaluation) study.

This interval-dependent antibody level varied by age, with those aged 45-54 years showing an 11-fold increase with a longer dosing interval (greater than 10 weeks vs 2-4 weeks). People younger than age 25 years showed a 13-fold increase with the longer interval, but participant numbers were low in this sub-group.

Overall antibody levels in infection-naive participants were 1268.72 Binding Antibody Units (BAU)/mL (1043.25 - 1542.91) in those with a 2-4-week interval compared to 11,479.73 BAU/mL (10,742.78 - 12,267.24) (P < .0001), in those with at least a 10-week interval between doses.

The work is the latest analysis from SIREN, which measured antibody levels in the blood from nearly 6000 healthcare workers from across the UK. Study lead Ashley Otter, PhD, technical lead for SIREN serology at the UK Health Security Agency (UKHSA), will present the work on Tuesday at this year's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Lisbon.

In an interview with Medscape Medical News, Otter noted that, "it is important to remember that antibody levels are only one aspect of the immune response and in our recent vaccine effectiveness analysis we found that dosing intervals did not affect protection against infection."

The study, which appeared in the March issue of the New England Journal of Medicine, also found that after the second dose of vaccine, there was about a 2.5-fold difference in antibody levels between those who had prior infection 16.052 (14.071-18.312) BAU/mL compared with 7.050 (6.634 - 7.491) BAU/mL in infection-naive individuals (P < .0001).

Following the first dose only, antibody levels were up to 10 times higher in participants who were previously infected compared with infection-naive individuals. This effect lasted up to 8 months and then began to plateau.

Natural Infection Increased Antibody Levels

Otter remarked that, "COVID-19 antibody levels are high in those people who were previously naturally infected and vaccinated, highlighting that vaccination provides an additional benefit to these individuals."

Medscape asked Charlotte Thålin, PhD, an immunologist from the Karolinska Institute, Stockholm, Sweden, to comment on the study. Thålin studies a cohort similar to SIREN, called the Swedish COMMUNITY healthcare worker cohort. "The new data from the SIREN emphasizes the importance of the number of antigenic exposures and the time interval between them, whether it be exposure through vaccination or exposure through infection."

"We see similar data in our Swedish COMMUNITY healthcare worker cohort," Thålin continued, "where infection prior to vaccination yields a more than twofold enhancement in antibodies, neutralizing breadth, and T-cell responses, and an even larger increase with a longer time interval between infection and vaccination."

However, she cautioned that they now see a high rate of Omicron vaccine breakthrough infections, and this is also true in people with previous infection and three vaccine doses.

"As we approach a second booster — a fourth vaccine dose — we need to consider that many individuals will have had up to five to six antigen exposures within a short period of time, sometimes within a year," she pointed out. "This is a whole new scenario, with a lot of different combinations of vaccine and infection-induced immunity. We do not yet know the impact of these frequent immune exposures, and we now need to monitor immune responses following Omicron and booster doses closely."

SIREN originally aimed to understand how much protection people got after developing a primary infection and why they might become reinfected with COVID-19. Following the rollout of the UK's vaccination program, the protective effects of vaccination against COVID-19 were investigated as well as why some people still become ill after being vaccinated, Otter explained.

In this latest analysis, Otter and colleagues assessed anti-spike binding antibodies in serum samples from a total of 5871 healthcare workers, with 3989 after one dose (at least 21 days) and 1882 two doses (at least 14 days).

Most participants were women (82.3%) and of white ethnicity (87%) and came from across the UK.

Participants were also categorized into those who had evidence of natural COVID-19 infection (confirmed by a PCR test or assumed because of their antibody profile) or those who were infection-naive. Almost all (>99%) of those who were infection-naive seroconverted after vaccination.

The primary outcome was anti-spike antibody levels assessed according to dose, previous infection, dosing interval, age, ethnicity, and comorbidities, including immunosuppressive disease such as immune system cancers, rheumatologic disease, chronic respiratory diseases, diabetes, obesity, and chronic neurologic disease.

In the infection-naive group, the mean antibody (anti-S titer) was 75.48 BAU/mL after the first vaccine dose one, and this rose to 7049.76 BAU/mL after the second dose.

The much higher antibody titer with the second dose in infection-naive individuals, "is what gives you the most protection, as your antibody titers are at their peak. They then start to gradually wane from this peak," said Otter.

In the post-infection group, antibody titers also rose (2111.08 BAU/mL after first dose and 16,052.39 BAU/mL after second dose), although less so than in the infection-naive group, because of the additional exposure of infection, added Otter.

Antibody levels also varied according to time elapsed between natural infection and dose 1 of vaccination. With a 3-month interval, antibody levels were 1970.83 (1506.01 - 2579.1) BAU/mL compared with 13,759.31 (8,097.78 - 23,379.09) BAU/mL after a 9-month interval. Antibody levels after one dose in those previously infected are higher than the infection-naive because "previous infection, then vaccination, is likely explained by T-cell expansion upon a boost with a second antigen exposure, and then a maturing memory B-cell response that has been demonstrated up to 6 months," explained Otter.

Timing of Fourth Dose

By March of this year, 86.2% of the UK population aged over 12 years had received at least two doses, but with rises in disease prevalence and the spread of variants of concern, further work is ongoing to understand the waning of the immune response, level of protection, and why some individuals develop COVID-19 even when double-vaccinated.

Medscape asked Susanna Dunachie, BMChB, professor of infectious diseases, University of Oxford, UK, what the interval findings might mean for the timing of the fourth dose of vaccine across the UK population.

In the UK, fourth doses are being given to people who are 75 years and older, residents in care homes for older people, and those with weakened immune systems. "To make decisions about fourth doses for healthy people, we need to see how quickly antibody and T-cell responses drop," said Dunachie, who is part of the large SIREN study team but was not involved in the analysis led by Otter. "Current research suggests that the T-cell response may be better maintained than the antibody response, and less affected by variants like Omicron."

She explained the balance between antibody and T-cell responses to vaccination. "It is likely that antibodies that neutralize the virus are important for preventing any infection at all, and these unfortunately do fall in time, but T-cell responses are better sustained and help keep people out of [the] hospital," she said.

Dunachie added that it was necessary to wait and observe what happens next with SARS-CoV-2 evolution, as well as wait for longer follow-up after the third dose in healthy people. "On current evidence, my estimate is we postpone decisions on fourth doses in healthy people to late summer/autumn."

32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID): Abstract 250. To be presented April 26, 2022.

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